Morgan Cattoor

 Introduction. Systemic lupus erythematosus (SLE) is a chronic autoimmune disease driven by aberrant responses in both innate and adaptive immunity.¹ Standard treatment consists of immunosuppressive agents such as corticosteroids, azathioprine, and methotrexate.²  When these therapies fail, mesenchymal stem cells (MSCs) offer promise: by modulating the immune system, they are able to notably suppress T cell proliferation and offer therapeutic benefit in lupus and other autoimmune diseases.^2,3,4 However, such therapy places MSCs in an inflammatory environment. Recent studies have drawn attention to the effect of inflammatory factors on MSC function.^4,5,6 The inflammatory mediator IFN-γ has been shown to initiate the increased 2,3-indolamine dioxygenase (IDO) expression of MSCs through a pathway involving PI3Ka and STAT1.⁵ IDO is responsible for the MSC inhibition of T-cell proliferation.⁴ Understanding the mechanisms behind MSC therapy in the context of various disease states is integral in harnessing their immunomodulatory ability. Methods. UC-MSCs and PBMCs (peripheral blood mononuclear cells) isolated from patients with active SLE were co-cultured with an inhibitor of the IDO enzyme (1-methyl-dl-tryptophan) and then CD4+T cells measured. CD4/CD8 cells were then separated, IDO and IFN- γ expression were quantified by Western Blot analysis, and antibody to IFN-γ added to assess effect on IDO production.⁴ In a second study, researchers performed knockdown of PI3K and STAT1 by siRNA transfection and resultant mRNA expression of IDO was determined by RT-PCR. Western Blot was used to analyze IFN-γ induced phosphorylation of STAT1.⁵ Results.  UC-MSCs significantly inhibit proliferation of CD4+25- T lymphocytes in lupus patients; furthermore; the IDO inhibitor reversed the suppression of lupus T-cell proliferation by the UC-MSCs.  IFN-γ from lupus CD8+ T-cells triggered allogenic MSCs to produce IDO and inhibit T cell proliferation. The increase in IDO activity was seen post MSC transplantation in lupus patients.⁴ Secondly, it was determined that PI3K is required for IFN-γ induced IDO production. STAT1 requires phosphorylation to be translocated to the nucleus, and IFN-γ stimulation caused this phosphorylation to occur. Overexpression of both players, PI3K and STAT1, increased IDO production.⁵ Conclusions. These studies highlight IFN-γ as the inflammatory factor that primes MSCs to function in the inhibition of T-cell proliferation in lupus patients. IFN-γ works through PI3K for the ultimate phosphorylation of the transcription factor STAT1, which in turn causes increased expression of IDO from MSCs and regulation of the immune system.^3,4,5. As MSCs show promise in clinical application, how they function within a SLE patient’s system should not be overlooked.⁷

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